Replacement of a Naphthalene Scaffold in Kelch-like ECH-Associated Protein 1 (KEAP1)/Nuclear Factor (Erythroid-derived 2)-like 2 (NRF2) Inhibitors.
Replacement of a Naphthalene Scaffold in Kelch-like ECH-Associated Protein 1 (KEAP1)/Nuclear Factor (Erythroid-derived 2)-like 2 (NRF2) Inhibitors.
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Kelch-like ECH-Associated Protein 1 (KEAP1)/Nuclear Factor (Erythroid-derived 2)-like 2 （NRF2）抑制剂中萘支架的替代研究
DOI：
10.1021/acs.jmedchem.8b01133
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发表时间：
2018-09-13
影响因子：
7.3
通讯作者：
Moore TW
中科院分区：
文献类型：
--
作者：
Richardson BG;Jain AD;Potteti HR;Lazzara PR;David BP;Tamatam CR;Choma E;Skowron K;Dye K;Siddiqui Z;Wang YT;Krunic A;Reddy SP;Moore TW
核因子-红细胞2相关因子2（NRF 2）的激活剂可能会导致有前途的治疗方法，用于预防和治疗氧化应激和炎症性疾病。转录因子NRF 2的泛素化和随后的降解由Kelch样ECH相关蛋白-1（KEAP 1）介导。KEAP 1/NRF 2与小分子相互作用的抑制导致NRF 2活化。以前，我们和其他人描述了基于萘的NRF 2激活剂，但1，4-二氨基萘支架可能不代表药物样支架。特别注意水溶性，代谢稳定性，效力和致突变性，我们修改了以前已知的，基于萘的非亲电NRF 2激活剂，得到一系列非萘和杂环支架。我们发现，与以前报道的萘基化合物相比，1，4-异喹啉支架提供了更好的致突变特性，而不会牺牲效力、稳定性或溶解性。
Activators of Nuclear factor-erythroid 2-related factor 2 (NRF2) could lead to promising therapeutics for prevention and treatment of oxidative stress and inflammatory disorders. Ubiquitination and subsequent degradation of the transcription factor NRF2 is mediated by Kelch-like ECH-associated protein-1 (KEAP1). Inhibition of the KEAP1/NRF2 interaction with small molecules leads to NRF2 activation. Previously, we and others described naphthalene-based NRF2 activators, but the 1,4-diaminonaphthalene scaffold may not represent a drug-like scaffold. Paying particular attention to aqueous solubility, metabolic stability, potency, and mutagenicity, we modified a previously known, naphthalene-based non-electrophilic NRF2 activator to give a series of non-naphthalene and heterocyclic scaffolds. We found that, compared to previously reported naphthalene-based compounds, a 1,4-isoquinoline scaffold provides a better mutagenic profile without sacrificing potency, stability, or solubility.
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DOI：
10.1039/c6cc08797c
发表时间：
2017-05-04
期刊：
Chemical communications (Cambridge, England)
影响因子：
--
作者：
Clulow JA;Storck EM;Lanyon-Hogg T;Kalesh KA;Jones LH;Tate EW
通讯作者：
Tate EW
影响因子：
16
作者：
Baird, Liam;Swift, Sam;Lleres, David;Dinkova-Kostova, Albena T.
通讯作者：
Dinkova-Kostova, Albena T.
影响因子：
10.5
作者：
Itoh, K;Wakabayashi, N;Yamamoto, M
通讯作者：
Yamamoto, M
影响因子：
7.3
作者：
Davies, Thomas G.;Wixted, William E.;Kerns, Jeffrey K.
通讯作者：
Kerns, Jeffrey K.
纳摩尔Keap1-Nrf2蛋白-蛋白相互作用抑制剂的构效关系及构效关系及探索性体内评价
影响因子：
7.3
作者：
Jiang, Zheng-Yu;Xu, Li-Li;You, Qi-Dong
通讯作者：
You, Qi-Dong